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  Use of a trioxopyrimidine for the treatment and prevention of bronchial inflammatory diseasesUSPTO Application #: 20070225253Title: Use of a trioxopyrimidine for the treatment and prevention of bronchial inflammatory diseases Abstract: The invention provides the use of a trioxopyrimidine compound having an inhibitory activity against MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14 defined as a) an IC50 value of less than 5 μM for MMP-2, MMP-9 and MMP-14 each; b) a ratio of more than 100 for the IC50 values of MMP-1:MMP-2, MMP-1: MMP-9, MMP-1:MMP-14; and c) a ratio of more than 10 for the IC50 values of MMP-3:MMP-2, MMP-3:MMP-9, MMP-3:MMP-14, for the manufacturing of a medicament for the treatment or prevention of bronchial inflammatory diseases. (end of abstract) Agent: Hoffmann-la Roche Inc. Patent Law Department - Nutley, NJ, US Inventor: Didier Cataldo USPTO Applicaton #: 20070225253 - Class: 514058000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, Polysaccharide, Dextrin Or Derivative The Patent Description & Claims data below is from USPTO Patent Application 20070225253. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to the use of a trioxopyrimidine compound for the treatment and prevention of bronchial inflammatory diseases. Introduction [0002] Matrix metalloproteases (MMPs) are a family of zinc- and calcium-dependent proteases that are capable of degrading the extracellular matrix (ECM) and basement membrane (Egeblad, M., and Werb, Z., Nat. Rev. Cancer 2 (2002) 161-174; Overall, C. M., and Lopez-Otin, C., Nat. Rev. Cancer 2 (2002) 657-672). They are believed to have pivotal roles in embryonic development and growth (Holmbeck, K., et al., Cell 99 (1999) 81-92; Vu, T. H., et al., Cell 93 (1998) 411-422) as well as in tissue remodeling and repair (Shapiro, S. D., Curr. Opin. Cell Biol. 10 (1998) 602-608; Lund, L. R., et al., EMBO J. 18 (1999) 4645-4656). Excessive or inappropriate expression of MMPs may therefore contribute to the pathogenesis of many tissue-destructive processes, including tumor progression (Egeblad, M., and Werb, Z., Nat. Rev. Cancer 2 (2002) 161-174; Overall, C. M., and Lopez-Otin, C., Nat. Rev. Cancer 2 (2002) 657-672) and aneurysm formation (Carmeliet, P., et al., Nat. Genet. 17 (1997) 439-444). MMP effects are far from being restricted to ECM degradation (Chang, C., and Werb, D., Trends Cell Biol. 11 (2001) S37-43). Peptide growth factors that are sequestered by ECM proteins become available once degraded by MMP-9 (Manes, S., et al., J. Biol. Chem. 274 (1999) 6935-6945). MMPs can increase the bioavailability of VEGF (Bergers, G., et al., Nat. Cell Biol. 2 (2000) 737-744) but also generate angiogenesis inhibitors such as angiostatin by cleavage of plasminogen (Dong, Z., et al., Cell 88 (1997) 801-810). [0003] Inhibition of MMPs, either with the naturally occurring Tissue Inhibitors of Metalloproteases (TIMPs), or with low molecular weight inhibitors, resulted in impressive anti-tumor and anti-metastatic effects in animal models (Brown, P. D., Med. Oncol. 14 (1997) 1-10). Most of the low-molecular weight inhibitors of MMPs are derived from the hydroxamic acid compound class and inhibit MMPs in a broad manner, being not selective for MMP-2 and MMP-9, the key MMPs in tumor invasion, metastatic spread, and angiogenesis. However, MMP inhibiting molecules from another structural class, the trioxopyrimidines, have been described, e.g. in WO 97/23465 and WO 01/25217. This class of compounds is extremely potent, and highly selective, with an almost exclusive specificity for MMP-2, MMP-9, while sparing most other members of the MMP family of proteases. [0004] Several MMP inhibitors, predominantly of the hydroxamic acid substance class with broad substrate specificity were, and in part still are, in clinical testing for anti-tumor treatment. All of the published clinical results with these inhibitors were disappointing, showing little or no clinical efficacy (Fletcher, L., Nat. Biotechnol. 18 (2000) 1138-1139). The reason for this lack of efficacy in the clinic most likely is the fact that patients could not be given high enough doses for anti-tumor or anti-metastatic activity because of the side effects associated with these broadly acting inhibitors. These dose-limiting side effects were predominantly arthralgias and myalgias (Drummond, A. H., et al., Ann. N. Y. Acad. Sci. 878 (1999) 228-235). As a possible way to circumvent this problem, the combination of MMP inhibitors with classical cytostatic/cytotoxic compounds was evaluated in animal studies. Indeed, in these experiments, MMP inhibitors, in combination with cytostatic/cytotoxic drugs, showed enhanced tumor inhibiting efficacy (Giavazzi, R., et al., Clin. Cancer Res. 4 (1998) 985-992). In addition, International patent application Ser. No. PCT/EP02/04744 shows the combination of trioxopyrimidine based gelatinase inhibitors and cytotoxic/cytostatic compounds such as cisplatin, Paclitaxel, Gemcitabine or Etoposide. [0005] There have been made a lot of attempts to identify compounds which prevent or inhibit bronchial inflammatory diseases. Inhaled synthetic glucocorticosteroids are widely used in the treatment of bronchial asthma where they provide very effective first line treatment. However, a range of unwanted side effects and the often complex dosing schedules associated with these drugs frequently result in poor patient compliance. Loteprednol etabonate, an inactive metabolite soft steroid, is being examined in clinical trials for its effects on airway inflammation (Szelenyi, I., et al., Drugs Today 36 (2000) 313-320). Ciclesonide, a pro-drug soft steroid, has demonstrated efficacy without side effects in a once daily formulation in asthma patients and is being developed for the treatment of both asthma and chronic obstructive pulmonary disease (Rohatagi, S., et al., J. Clin. Pharmacol. 43 (2003) 365-378). [0006] Therefore, there exists a need for highly potent substances which can be used for the treatment or prevention of bronchial inflammatory diseases. Description of the Invention [0007] It was surprisingly found that trioxopyrimidine-based MMP inhibitors which are highly selective for MMP-2, MMP-9 and MMP-14 are useful for the treatment or prevention of bronchial inflammatory diseases. [0008] The invention therefore provides the use of a trioxopyrimidine compound having an inhibitory activity against MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14 defined as [0009] a) an IC.sub.50 value of less than 5 .mu.M for MMP-2, MMP-9 and MMP-14 each; [0010] b) a ratio of more than 100 for the IC.sub.50 values of MMP-1:MMP-2, MMP-1: [0011] MMP-9, MMP-1:MMP-14; and [0012] c) a ratio of more than 10 for the IC.sub.50 values of MMP-3:MMP-2, MMP-3: MMP-9, MMP-3:MMP-14, for the treatment of prevention of bronchial inflammatory diseases in a host mammal in need of such treatment. [0013] IC.sub.50 values are measured by an in vitro assay for MMP enzymatic activity. Such an assay is described by Stack, M. S., and Gray, R. D., J. Biol. Chem. 264 (1989) 4277-4281. This assay is based on the determination of MMP enzymatic activity on a dinitrophenol substrate and fluorescence measurement of the substrate after cleaving by MMPs. [0014] The invention further provides the use of such trioxopyrimidine compounds for the manufacturing of a medicament for the treatment of bronchial inflammatory diseases in a patient suffering from such a disease. [0015] Matrix metalloproteinases are well-Known in the state of the art and are defined, e.g., by their EC numbers (MMP-1 EC 3.4.24.7; MMP-2 EC 3.4.24.24; MMP-3 EC 3.4.24.17, MMP-9 EC 3.4.24.35, MMP-14 EC 3.4.24). [0016] Trioxopyrimidines useful for the invention are compounds from a well-known structural class. Such compounds are described in, for example, U.S. Pat. Nos. 6,242,455 and 6,110,924; WO 97/23465, WO 98/58915, WO 01/25217, which are incorporated herein by reference, and Grams, F., et al., Biol. Chem. 382 (2001) 1277-1285, and are effective and highly selective for MMP-2, MMP-9, and MMP-14. [0017] According to the invention, the following compounds are particularly preferred: [0018] 5-Biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]pyrimidine-2,4,6-tri- one (Compound I) [0019] 5-(4-Phenoxy-phenyl)-5-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrimidine-2,4,6- -trione (Compound II) [0020] 5-[4-(4-Chloro-phenoxy)-phenyl]-5-(4-pyrimidin-2-yl-piperazin-1-yl) -pyrimidine-2,4,6-trione (Compound III) [0021] 5-[4-(3,4-Dichloro-phenoxy)-phenyl]-5-(4-pyrimidin-2-yl-piperazin-1-yl) -pyrimidine-2,4,6-trione (Compound IV) [0022] 5-[4-(4-Bromo-phenoxy)-phenyl]-5-(4-pyrimidin-2-yl-piperazin-1-yl) -pyrimidine-2,4,6-trione (Compound V). [0023] According to the invention the trioxopyrimidine-based inhibitors have to be administered to the patient suffering from such a disease, over several months or years (especially in case of prevention), to the patient in need of such a therapy. The trioxopyrimidine compounds are administered preferably as sprays, with non-toxic doses ranging between micro and nanomolar concentrations. [0024] The invention relates to a method used for treating bronchial inflammatory diseases, preferably asthma and chronic obstructive pulmonary disease (COPD) in a host mammal in need of such treatment, e.g., a patient suffering from such a disease, by the application of a trioxopyrimidine compound according to the invention to a patient in a pharmaceutically effective amount. Asthma is an inflammatory disease of the bronchial tree related or not to an allergen exposure. This inflammation provokes symptoms in patients by stimulating the bronchial smooth muscles to contract, enhancing the mucus secretion, and inducing bronchial morphological changes thought to be an aggravating factor regarding the course of the disease. Airway hyperresponsiveness is a hallmark of the disease and is responsible for most of symptoms. Bronchial tree is a very complex tissue with many cell types (epithelial cells, smooth muscle cells, inflammatory cells, nerves, mucus producing cells, fibroblasts, and the like) and the bronchial remodelling events which comprise many aspects mainly consist in a deposition of extracellular matrix components in the bronchial walls and an hyperplasia of the mucus producing cells. The use of trioxopyrimidine compounds according to the invention inhibits the inflammatory cells influx in the compartments of bronchoalveolar lavage and peribronchial tissue and inhibits the hyperresponsiveness defined as an abnormal response to stimulating agents such as methacholine. The disease and current treatments are reviewed in, e.g., GINA Workshop Report, Global Strategy for Asthma Management and Prevention (NIH Publication No. 02-3659) and Fabbri, L. M., and Hurd, S. S., Eur. Respir. J. 22 (2003) 1-2. [0025] The invention therefore further relates to a method for treating bronchial inflammatory diseases in a patient suffering from such a disease, using a trioxopyrimidine compound according to the invention in a therapeutically effective amount. [0026] The invention preferably further relates to a method for treating emphysema in a patient suffering from such a disease, using trioxopyrimidine compounds according to the invention. In such a disease, the alveolar walls are destroyed by proteolytic processes and this destruction impairs the transfer of oxygen to the blood. Physiological problems also occurs because of the derived hyperinflation which causes abnormalities in the ventilation by causing a dysfunction of respiratory muscles and because of a hypertension in pulmonary arteries leading to cardiac failure in advanced stages. [0027] According to the invention the trioxopyrimidine compound has to be administered over several months or years, to the patient in need of such a therapy. The trioxopyrimidine compounds are administered preferably by the aerosolization of a liquid or powder formulation, with non-toxic doses ranging between micro and nanomolar concentrations per kg and day. [0028] The exact dosage of the MMP inhibitors will vary, but can be easily determined. In general, the preferred daily dosage of the inhibitors will range between 1 .mu.mol/kg and day to 100 nmol/kg and day. [0029] The pharmaceutical compositions are aqueous compositions having physiological compatibility. The compositions include, in addition, auxiliary substances, buffers, preservatives, solvents and/or viscosity modulating agents. Appropriate buffer systems are based on sodium phosphate, sodium acetate or sodium borate. Preservatives are required to prevent microbial contamination of the pharmaceutical composition during use. Suitable preservatives are, for example, benzalkonium chloride, chlorobutanol, methylparabene, propylparabene, phenylethyl alcohol, sorbic acid. Such preservatives are used typically in an amount of 0.01 to 1% weight/volume. [0030] Suitable auxiliary substances and pharmaceutical formulations are described in Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Co., edited by Oslo et al. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of a pharmaceutically acceptable substances include saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Continue reading... Full patent description for Use of a trioxopyrimidine for the treatment and prevention of bronchial inflammatory diseases Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Use of a trioxopyrimidine for the treatment and prevention of bronchial inflammatory diseases patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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